The long-term goal of this research is to elucidate the molecular basis of mechanotransduction by mammalian somatosensory neurons. Somatosensory mechanoreceptors mediate the senses of pain, touch and proprioception. The importance of these senses to human health is underscored by diseases that cause peripheral neuropathy, such as rheumatoid arthritis, diabetes and acquired immunodeficiency syndrome. Because patients with peripheral neuropathy cannot feel injuries, even minor insults can lead to irreversible tissue damage and chronic pain. The objective of this exploratory study is to understand how cell surface receptors and ion channels detect mechanical stimuli and transduce this information into physiological changes at the cellular level. A combination of molecular genetic, histological, and electrophysiological, and live-cell imaging methods will be used to probe the mechanisms whereby stretch, changes in osmolarity or direct pressure lead to depolarization of the primary afferent neuron. One of the major goals of this application is to develop in vitro systems that can be used to simultaneously detect and characterize mechanosensory responses in large numbers of cultured sensory neurons from rat dorsal root or trigeminal ganglia. Histological and pharmacological analyses will then be used to profile mechanosensitive cells with respect to the expression of a variety of molecular markers that delineate subsets of primary afferent neurons. Furthermore, we will use the high-throughput stimulus paradigms and detection methods developed here to carry out a screen to identify molecules that may be involved in mechanosensory transduction. Once identified, candidate molecules will be evaluated using electrophysiological, histological and genetic methods. [unreadable] [unreadable]